PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia worldwide. In the US, it is the fifth leading cause of death in people over 65 years of age. Delineating factors that predict rate of future cognitive decline and dementia are important but are yet to be thoroughly understood. It is now well recognized that there is substantial clinical heterogeneity among patients with AD. This heterogeneity particularly in rate of AD progression entails a significant challenge in designing and evaluating clinical trials for a new generation of AD therapies. Molecular factors that drive this heterogeneity are still poorly characterized. Several post translational modifications (PTMs) of A? protein have been noted to impact the rate of A? aggregation and its toxicity in animal models and thereby potentially impact AD progression. Studies on animal and in vitro models of AD and brain autopsy specimens have noted pyroglutamylated A? PTMs as relating to synaptic dysfunction and neuroinflammation. Among humans, the role for pyroglutamylated A? in impacting future rate of cognitive decline is unknown. The research at the foundation of this RO3 is a clinical translational study that aims to characterize the levels pyroglutamylated A? at the preclinical stage of AD among humans, in relation to neuroinflammation markers, synaptic markers and neurodegeneration markers to understand their impact on the rate of cognitive decline. This RO3 will help us specifically evaluate the role for pyroglutamylated A? on future rate of cognitive decline among normal cognition subjects at the preclinical stage of AD. We hypothesize that those subjects with higher levels of pyroglutamylated A? at baseline in the CSF or plasma will have higher levels of synaptic markers, and neuroinflammatory response contributing to faster cognitive decline over two years. By concurrently evaluating the neuroinflammatory, synaptic and neurodegeneration related markers longitudinally, we will develop a mechanistic model of pyroglutamylated A?'s impact on cognition in preclinical AD. Knowledge of biological factors that drive AD progression among humans will be critical in designing novel therapeutic strategies to prevent cognitive decline. This R03 will also help provide additional training and research opportunities in proteomics for Dr. Pillai to advance his clinical research skills to address a current knowledge gap in the molecular factors impacting in AD progression. The long-term goal of Dr. Pillai is to establish a programmatic body of research using bioinformatics and proteomics tools to delineate the molecular factors that underpin disease progression among neurodegenerative diseases and develop therapeutic strategies.